The Mount Sinai School of Medicine (MSSM) Alzheimer Disease Research Center (ADRC) continues its commitment to characterize, diagnose, and treat individuals with cognitive decline and dementia. The center is committed to finding causes, treatments, and means of preventing the disease, while also minimizing the emotional and economic cost of care. MSSM ADRC is dedicated to the identification of the clinical and biological benchmarks representing clinical and molecular endophenotypes. Our goal is to provide investigators with a wide distribution of: (a) well characterized patients with AD and other dementias, (b) individuals with MCI, a possible prodromal condition to dementia, and (c) healthy elders for research studies We focus on the very elderly and minority populations, and we have planned studies to insure that they are well-represented in our research efforts. We will assist the broadest community of investigators in accessing populations for clinical investigations (including studies to develop novel biomarkers for diagnosis and disease progression) and in conducting clinical trials of new agents. We will collaborate with the Departments of Psychiatry, Neurology, and Neuroscience in order to stimulate cutting-edge science to address the etiology and pathogenesis of AD. The environment and support provided in our last funding period has resulted in actively funded research projects as well as soon to-be-submitted proposals, all of which draw upon material and expertise from the ADRC Cores. This is evidenced in the three new ADRC Projects proposed herein, all of which feature junior investigators as Project Leaders or Co-Leaders. These Projects are highly innovative and highly integrated with each other and share the endophenotyping theme. As a group, the Projects all focus on aspects of the gamma- secretase reaction, the final step in amyloid beta generation. We will provide core resources and scientific environment to insure the growth of research in AD and related disorders. We will maximize the visibility of our center and its staff and activities in order to raise awareness of the disease We propose to continue our efforts to bring new perspectives to the problem of AD by fostering the growth of new junior researchers and recruiting researchers from other specialty areas into AD-related studies.